Brief History of Development

The French pharmaceutical company Laboratoires Meram began clinical development and testing of acamprosate in 1982. From 1982 to 1988, acamprosate was tested for safety and for efficacy as a treatment for alcohol dependence. Based on these studies, in 1989 Laboratoires Meram was granted marketing authorization for acamprosate in France under the trade name Aotal^®. Since then, acamprosate has been extensively used and studied throughout Europe and, subsequently, in the United States.

Although acamprosate has been used in Europe for more than 20 years, it was not approved by FDA until July 2004. Acamprosate became available for use in the United States in January 2005, under the trade name Campral^® Delayed-Release Tablets (Merck Santé, a subsidiary of Merck KGaA, Darmstadt, Germany). Campral is currently marketed in the United States by Forest Pharmaceuticals.

Pharmacology

Acamprosate's action in maintenance of alcohol abstinence is not completely understood, but evidence indicates that acamprosate interacts with the glutamate neurotransmitter system, reducing and normalizing the pathologic glutamatergic hyperactivity that occurs during protracted withdrawal from alcohol. It is hypothesized that this normalization leads to a reduction of common symptoms of protracted, or postacute, withdrawal such as insomnia, anxiety, and restlessness—symptoms that may contribute to a patient's return to alcohol use (reviewed by Litten, Fertig, Mattson, & Egli, 2005; Myrick & Anton, 2004; Thomson Healthcare, Inc., 2006). Chick, Lehert, and Landron (2003) have proposed that patients who returned to drinking while taking acamprosate drank less, and less frequently, than those taking placebo.

The bioavailability of acamprosate after oral administration is approximately 11 percent, and stable plasma concentrations are reached within 5 days of taking the medication. Acamprosate is not metabolized and is excreted primarily by the kidneys as acamprosate.

Efficacy

Considerable evidence supports the efficacy of acamprosate in the treatment of alcohol use disorders (AUDs). Numerous European trials have found acamprosate significantly more effective than placebo in reducing drinking days, increasing complete abstinence, and lengthening time to relapse. Evidence from U.S. studies has been mixed. The Combining Medications and Behavioral Interventions (COMBINE) study did not find acamprosate to be more effective than placebo (Anton et al., 2006). However, some analyses and reviews have concluded otherwise (although these analyses did not include data from the COMBINE study). A meta-analysis (an analysis of the outcome data of multiple individual studies) of European studies concluded that acamprosate is moderately effective in achieving and maintaining abstinence (Bouza, Magro, Muñoz, & Amate, 2004). This analysis of 12 studies found that acamprosate increased the continuous abstinence rate and doubled continuous abstinence duration compared with placebo. Similarly, a review of clinical trials by Mann (2004) concluded that acamprosate is more effective than placebo in the short and long term. Mason and colleagues (2006) found acamprosate to be superior to placebo only when controlling for patient characteristics associated with treatment efficacy. They also found acamprosate superior to placebo for a subgroup of patients motivated to achieve total abstinence.

Methodological differences between U.S. and European studies may account for differing results. These differences have included the following:

• Duration of pretreatment abstinence required
• Duration of treatment (European studies tended to be longer than U.S. studies)
• Concomitant medications allowed (European studies tended to be more flexible in allowing medications than U.S. studies)
• Nature and intensity of psychosocial treatment (U.S. studies tended to have more standardized and intensive psychosocial treatments)
• Outcome measures used
• Severity of participants' AUDs.

A thorough discussion of acamprosate efficacy studies is in this TIP's online literature review.

Safety

Acamprosate has a good safety profile:

• Patients maintained on acamprosate have not developed tolerance for or dependence on it, and it appears to have no potential for abuse.
• It carries virtually no overdose risk; even at overdoses up to 56 grams (a normal daily dose is 2 grams), acamprosate was generally well tolerated by patients (Thomson Healthcare, Inc., 2006).
• Most side effects are mild and transient, lessening or disappearing within the first few weeks of treatment (diarrhea tends to persist).
• Although there is a pharmacokinetic interaction by which acamprosate can increase naltrexone blood levels, there are no other clinically significant interactions between acamprosate and other medications (Johnson et al., 2003).

Acamprosate also has advantages over other medications for treating AUDs in some patients:

• Because acamprosate is not metabolized by the liver, it can be used safely even by patients with severe liver disease, unlike oral or injectable naltrexone or disulfiram.
• Because it does not affect endogenous or exogenous opioids, it can be used with patients receiving opioid maintenance therapy (reviewed by Myrick & Anton, 2004) or undergoing treatment with opioids for acute or chronic pain, unlike oral or injectable naltrexone.
• Because acamprosate does not interact with benzodiazepines or other medications used in medical detoxification, it can be continued safely if a patient returns to drinking and subsequently requires detoxification.

Initiating Treatment With Acamprosate

Acamprosate is typically initiated 5 days following drinking cessation. However, acamprosate can be used safely with alcohol (and with benzodiazepines), and it can be started during medically supervised withdrawal. Acamprosate therapy should be maintained if a patient relapses to alcohol use. Acamprosate reaches full effectiveness in 5 to 8 days.

Before initiating treatment, healthcare practitioners should do the following:

• Conduct or refer patients for a thorough medical exam and assessment (as described in Chapter 6—Patient Management).
• Perform renal function tests (a standard panel for urea, electrolytes, and serum creatinine) to rule out severe renal impairment.

Side Effects, Contraindications, and Cautions

Exhibit 2-1 lists acamprosate's side effects. The most common side effect of acamprosate is diarrhea. This and other side effects are usually mild and resolve quickly. In some patients, diarrhea is severe and persistent. Patients should be instructed not to discontinue acamprosate if they experience side effects and to inform their prescribing professional.

Exhibit 2-2 lists acamprosate contraindications, and Exhibit 2-3 lists cautions.

Patient Management

Ways for managing adverse reactions to acamprosate are listed in Exhibit 2-4.

There is no evidence that acamprosate impairs renal function. Followup laboratory work is not necessary unless evidence of renal impairment exists at treatment initiation.

Patient Education

In addition to giving patients the general patient education guidelines discussed in Chapter 6, healthcare providers should ensure that patients taking acamprosate know the following:

• The benefits and limitations of acamprosate
• What to expect—
  • Possible side effects
  • Full effectiveness in 5–8 days
• For women of childbearing age, the importance of using an effective birth control method
• To continue taking acamprosate if a slip or relapse occurs and to inform their prescribing professional immediately
• To notify the prescribing professional immediately if they begin to have suicidal thoughts, if they begin to feel depressed, or if an existing depression worsens
• That tablets should not be crushed
• Not to take extra medication if a dose is missed and it is time to take the next dose.